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Article ; Online: The end of the beginning: application of single-cell sequencing to chronic lymphocytic leukemia.

Nagler, Adi / Wu, Catherine J

2022 Volume 141, Issue 4, Page(s) 369–379

Abstract: Single-cell analysis has emerged over the past decade as a transformative technology informative for the systematic analysis of complex cell populations such as in cancers and the tumor immune microenvironment. The methodologic and analytical ... ...

Abstract	Single-cell analysis has emerged over the past decade as a transformative technology informative for the systematic analysis of complex cell populations such as in cancers and the tumor immune microenvironment. The methodologic and analytical advancements in this realm have evolved rapidly, scaling from but a few cells at its outset to the current capabilities of processing and analyzing hundreds of thousands of individual cells at a time. The types of profiling attainable at individual cell resolution now range from genetic and transcriptomic characterization and extend to epigenomic and spatial analysis. Additionally, the increasing ability to achieve multiomic integration of these data layers now yields ever richer insights into diverse molecular disease subtypes and the patterns of cellular circuitry on a per-cancer basis. Over the years, chronic lymphocytic leukemia (CLL) consistently has been at the forefront of genomic investigation, given the ready accessibility of pure leukemia cells and immune cells from circulating blood of patients with this disease. Herein, we review the recent forays into the application of single-cell analysis to CLL, which are already revealing a new understanding of the natural progression of CLL, the impact of novel therapies, and the interactions with coevolving nonmalignant immune cell populations. As we emerge from the end of the beginning of this technologic revolution, CLL stands poised to reap the benefits of single-cell analysis from the standpoints of uncovering fresh fundamental biological knowledge and of providing a path to devising regimens of personalized diagnosis, treatment, and monitoring.
MeSH term(s)	Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/pathology ; Tumor Microenvironment/genetics ; Transcriptome
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2021014669
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Uh III Zs.140: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 364: Show issues

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Article ; Online: Mechanisms of immune activation and regulation: lessons from melanoma.

Kalaora, Shelly / Nagler, Adi / Wargo, Jennifer A / Samuels, Yardena

Nature reviews. Cancer

2022 Volume 22, Issue 4, Page(s) 195–207

Abstract: Melanoma, a skin cancer that develops from pigment cells, has been studied intensively, particularly in terms of the immune response to tumours, and has been used as a model for the development of immunotherapy. This is due, in part, to the high ... ...

Abstract	Melanoma, a skin cancer that develops from pigment cells, has been studied intensively, particularly in terms of the immune response to tumours, and has been used as a model for the development of immunotherapy. This is due, in part, to the high mutational burden observed in melanomas, which increases both their immunogenicity and the infiltration of immune cells into the tumours, compared with other types of cancers. The immune response to melanomas involves a complex set of components and interactions. As the tumour evolves, it accumulates an increasing number of genetic and epigenetic alterations, some of which contribute to the immunogenicity of the tumour cells and the infiltration of immune cells. However, tumour evolution also enables the development of resistance mechanisms, which, in turn, lead to tumour immune escape. Understanding the interactions between melanoma tumour cells and the immune system, and the evolving changes within the melanoma tumour cells, the immune system and the microenvironment, is essential for the development of new cancer therapies. However, current research suggests that other extrinsic factors, such as the microbiome, may play a role in the immune response to melanomas. Here, we review the mechanisms underlying the immune response in the tumour and discuss recent advances as well as strategies for treatment development.
MeSH term(s)	Humans ; Immunotherapy ; Melanoma/genetics ; Skin Neoplasms/pathology ; Tumor Escape/genetics ; Tumor Microenvironment
Language	English
Publishing date	2022-02-01
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/s41568-022-00442-9
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Zs.A 5563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Fecal microbiota transplantation in capsules for the treatment of steroid refractory and steroid dependent acute graft vs. host disease: a pilot study.

Youngster, Ilan / Eshel, Adi / Geva, Mika / Danylesko, Ivetta / Henig, Israel / Zuckerman, Tsila / Fried, Shalev / Yerushalmi, Ronit / Shem-Tov, Noga / Fein, Joshua A / Bomze, David / Shimoni, Avichai / Koren, Omry / Shouval, Roni / Nagler, Arnon

Bone marrow transplantation

2024 Volume 59, Issue 3, Page(s) 409–416

Abstract: Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) ...

Abstract	Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.
MeSH term(s)	Humans ; Fecal Microbiota Transplantation/adverse effects ; Pilot Projects ; Prospective Studies ; Gastrointestinal Tract ; Hematopoietic Stem Cell Transplantation/adverse effects ; Graft vs Host Disease/etiology ; Steroids
Chemical Substances	Steroids
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	632854-4
ISSN	1476-5365 ; 0268-3369 ; 0951-3078
ISSN (online)	1476-5365
ISSN	0268-3369 ; 0951-3078
DOI	10.1038/s41409-024-02198-2
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Article ; Online: Salivary malignancies- medical, demographic and diagnostic analysis.

Israel, Yair / Rachmiel, Adi / Gourevich, Konstantin / Nagler, Rafael

Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery

2019 Volume 47, Issue 3, Page(s) 500–504

Abstract: We examined systemic medical and demographic characteristics of patients diagnosed with salivary malignant tumors in order to better understand the pathogenesis of the disease. Of 101 patients who received definitive treatment for malignant salivary ... ...

Abstract	We examined systemic medical and demographic characteristics of patients diagnosed with salivary malignant tumors in order to better understand the pathogenesis of the disease. Of 101 patients who received definitive treatment for malignant salivary gland tumors in our medical center, 22 died with disease (DwD) and were compared with the remaining 79 patients (Other). Mean ages were 66.7 years (median 68.0) in DwD group and 58.7 years (median 59.0) in the Others. The difference is significant (p = 0.037). Mucoepidermoid carcinoma was the diagnosis in 27.3% of DwDs and 27.8% of the others, Adenoidcystic carcinoma in 36.4% vs 21.5%, SCC and Acinic cell carcinoma were diagnosed in 18.3% vs 7.6% and 4.6% vs 7.6%, respectively. Alcohol consumption, concomitant malignancies, and chronic illnesses other than hypertension, were similar in the two groups, but hypertension (63.6%) in the DwD group was significantly higher than in the Other group (26.6%), (p = 0.0010). Smoking was also significantly different between the two groups: 50% of the DwD vs. 27.9% of the Others group smoked cigarettes. Similar distribution of the various malignant tumors in both groups emphasizes the relative importance of systemic factors such as smoking, aging and hypertension, in the salivary carcinogenesis process.
MeSH term(s)	Age Factors ; Aged ; Alcohol Drinking/adverse effects ; Alcohol Drinking/epidemiology ; Carcinoma, Acinar Cell/mortality ; Carcinoma, Acinar Cell/pathology ; Carcinoma, Adenoid Cystic/mortality ; Carcinoma, Adenoid Cystic/pathology ; Carcinoma, Mucoepidermoid/mortality ; Carcinoma, Mucoepidermoid/pathology ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Risk Factors ; Salivary Gland Neoplasms/mortality ; Salivary Gland Neoplasms/pathology ; Sex Factors ; Smoking/adverse effects ; Smoking/epidemiology ; Survival Rate
Language	English
Publishing date	2019-01-11
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	91267-0
ISSN	1878-4119 ; 1010-5182 ; 0301-0503
ISSN (online)	1878-4119
ISSN	1010-5182 ; 0301-0503
DOI	10.1016/j.jcms.2019.01.006
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Article ; Online: Survival Probabilities Related to Histology, Grade and Stage in Patients With Salivary Gland Tumors.

Israel, Yair / Rachmiel, Adi / Gourevich, Konstantin / Nagler, Rafael

Anticancer research

2019 Volume 39, Issue 2, Page(s) 641–647

Abstract: Background: The diversity of malignant salivary gland tumors challenges the study of survival rates. The current study evaluated patient survival rates using Kaplan-Meier analysis and examined the relative effects of histology, grade and stage on ... ...

Abstract	Background: The diversity of malignant salivary gland tumors challenges the study of survival rates. The current study evaluated patient survival rates using Kaplan-Meier analysis and examined the relative effects of histology, grade and stage on survival. Materials and methods: Using the Kaplan-Meier model, cancer-specific (CSS) and disease-free (DFS) survival probabilities were calculated as a function of time. Results: Of 101 patients, 79 survived and 22 died of their disease. The probability of CSS was 0.83, 0.73 and 0.61 at 5, 10 and 15 years, respectively; corresponding probability of DFS was 0.69, 0.59 and 0.54, respectively. Conclusion: CSS and the DFS probabilities in patients with salivary malignancies were quite high at 5 years, although these rates dropped over the long-term; the lethal effect of the malignancy is often delayed and prolonged. Tumor histology, grade and stage are well established factors in predicting prognosis. Although the subgroups of patients with MECA and SCC were too small to allow adequate statistical analysis, clear tendencies for devastating effects of poor differentiation in SCC and higher grade in MECA were shown. That is, 2/4 patients with high-grade MECA died from their disease, while only 1/15 with low-intermediate grade MECA died from their disease. Similarly, 2/4 patients with poorly differentiated SCC died from their disease, while only 1/5 with well-to-moderately-differentiated SCC died from their disease. Factors such as molecular markers should be further studied in an effort to improve prognosis prediction.
MeSH term(s)	Cell Differentiation ; Disease-Free Survival ; Genetic Markers/genetics ; Humans ; Kaplan-Meier Estimate ; Neoplasm Grading ; Neoplasm Staging ; Probability ; Prognosis ; Retrospective Studies ; Salivary Gland Neoplasms/metabolism ; Salivary Gland Neoplasms/mortality ; Salivary Gland Neoplasms/pathology ; Survival Rate
Chemical Substances	Genetic Markers
Language	English
Publishing date	2019-01-24
Publishing country	Greece
Document type	Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.13158
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Zs.A 1642: Show issues

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Article ; Online: Mortality rates and prognostic factors in patients with malignant salivary tumors.

Israel, Yair / Rachmiel, Adi / Gourevich, Konstantin / Nagler, Rafael

Medical oncology (Northwood, London, England)

2019 Volume 36, Issue 7, Page(s) 65

Abstract: Malignancies of the salivary glands represent a multifarious disease. Evaluating the prognostic factors of these malignancies may help predict patient outcome and aid decision-making in choosing the most suitable therapy. We examined the role of various ... ...

Abstract	Malignancies of the salivary glands represent a multifarious disease. Evaluating the prognostic factors of these malignancies may help predict patient outcome and aid decision-making in choosing the most suitable therapy. We examined the role of various salivary tumorigenic, clinical and therapeutic features in a cohort of 101 patients diagnosed and treated for primary malignant salivary tumors. These include histo-pathological diagnosis, stage, grade and T, N, M values as well as the existence of perineural invasion and extra-parenchymal spread. We also identified the salivary gland involved, the sub-compartment specific location of the tumor and the therapy administered. All these were related to mortality. Of the 101 patients examined, 79 survived and 22 died due to the disease. Tumor staging, distant metastasis and perineural invasion were highly significant predictors of increased lethality. Histo-pathological grading was also a predictor but to a lesser degree. Neither neck metastasis nor tumor size or type had a significant impact on lethality. Performing neck dissections did not decrease lethality rate. Location of the tumor in the parotid gland and more so in its deep lobe adversely affected lethality; extra-parenchymal spread also had an adverse effect. Our results seem to indicate hematogenous rather than lymphogenous spread of metastasis from malignant salivary tumors. The highest therapeutic priority should be achieving full local control of the disease by safe removal of the primary salivary tumor, accompanied by regional control of perineural invasion and extra-parenchymal spread and appropriate systemic treatment aimed at eradicating distant metastasis.
MeSH term(s)	Humans ; Israel/epidemiology ; Neoplasm Staging ; Parotid Neoplasms/mortality ; Parotid Neoplasms/pathology ; Parotid Neoplasms/therapy ; Prognosis ; Salivary Gland Neoplasms/mortality ; Salivary Gland Neoplasms/pathology ; Salivary Gland Neoplasms/therapy
Language	English
Publishing date	2019-06-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	1201189-7
ISSN	1559-131X ; 0736-0118 ; 1357-0560
ISSN (online)	1559-131X
ISSN	0736-0118 ; 1357-0560
DOI	10.1007/s12032-019-1284-y
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Article ; Online: Non-primary salivary malignancies: A 22-year retrospective study.

Israel, Yair / Rachmiel, Adi / Gourevich, Konstantin / Nagler, Rafael

Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery

2019 Volume 47, Issue 9, Page(s) 1351–1355

Abstract: Purpose: Most salivary gland malignancies are primary tumors, but in our medical center one of six is non-primary. The relative scarcity of such reports justifies studying them.: Subjects & methods: We studied patients' demographic and clinical ... ...

Abstract	Purpose: Most salivary gland malignancies are primary tumors, but in our medical center one of six is non-primary. The relative scarcity of such reports justifies studying them. Subjects & methods: We studied patients' demographic and clinical parameters, salivary tumors/metastasis, diagnosis and treatment, and survival rates. Results: Of all our salivary malignancy patients over the last 22 years, 15% (18/119) had non-primary malignant tumors, all located in the parotid glands. Of these, nine had skin cancer (SCC), 3 malignant solid tumors and 6 hematological systemic malignancies. Four had concomitant second malignancy. Mean age was 70.2 ± 13.8 years, 66.7% of the patients were males, 27.8% were smokers, none reported alcohol use. The most prevalent diagnostic tools used were CT (16 patients), FNA (13) and PET-CT (12). Eleven of 18 patients died from the disease despite receiving therapy: 6 SCC patients, 2 CLL patients and all 3 with solid tumors. All four lymphoma patients survived as did another three SCC patients. Conclusions: Chemotherapy and radiotherapy for systemic disease prolonged life rather than surgery. Patients with poor prognosis non-primary salivary tumors should be treated conservatively; surgery should be for those without widespread metastases or systemic disease. Sometimes a palliative patient may benefit from tumor debulking.
MeSH term(s)	Aged ; Aged, 80 and over ; Female ; Humans ; Lymphoma ; Male ; Middle Aged ; Positron Emission Tomography Computed Tomography ; Retrospective Studies ; Salivary Gland Neoplasms ; Survival Rate
Language	English
Publishing date	2019-07-03
Publishing country	Scotland
Document type	Journal Article
ZDB-ID	91267-0
ISSN	1878-4119 ; 1010-5182 ; 0301-0503
ISSN (online)	1878-4119
ISSN	1010-5182 ; 0301-0503
DOI	10.1016/j.jcms.2019.06.018
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Article ; Online: Kaplan-Meier analysis of salivary gland tumors: prognosis and long-term survival.

Israel, Yair / Rachmiel, Adi / Gourevich, Konstantin / Nagler, Rafael

Journal of cancer research and clinical oncology

2019 Volume 145, Issue 8, Page(s) 2123–2130

Abstract: Purpose: We evaluated the impact of various tumor related parameters on survival probability in a cohort of patients with malignant salivary tumors, using the Kaplan-Meier analysis.: Methods: We measured patients up to 15 years following therapy, ... ...

Abstract	Purpose: We evaluated the impact of various tumor related parameters on survival probability in a cohort of patients with malignant salivary tumors, using the Kaplan-Meier analysis. Methods: We measured patients up to 15 years following therapy, looking at T N M stage, grade perineural invasion and extra-parenchymal spread. Results: Of 101 patients diagnosed with various salivary malignant tumors in our medical center, 79 patients survived while 22 died with disease (DWD). The impact of distant metastasis (M+) was devastating (survival probability at 60 months and at 180 months dropped from 0.93 (M-) to 0.40 (M+) and from 0.67 to 0.40, respectively, p = 0.0001), the impact of perineural invasion was severe (at 180 months the probability of survival dropped from 0.75 to 0.21, p = 0.002). Higher stage tumor also decreased survival (from 0.82 to 0.53 at 180 months, p = 0.002) as did poor histological grade (from 0.85 to 0.48 at 180 months, p = 0.019). Neck metastasis (N+) impact was quite moderate (at 180 months the probability of survival dropped from 0.69 to 0.58, p = 0.044) while neither tumor size (T) nor extra-parenchymal spread significantly affected survival. Conclusions: Salivary tumor location and its potential to infiltrate nerves and blood vessels and to metastasize is the most telling parameter. Systemic therapy aimed at halting distant metastatic spread is the most effective therapeutic goal. Dissection of N0 neck metastasis is not necessarily a valuable treatment.
MeSH term(s)	Carcinoma, Adenoid Cystic/diagnosis ; Carcinoma, Adenoid Cystic/mortality ; Carcinoma, Adenoid Cystic/pathology ; Carcinoma, Mucoepidermoid/diagnosis ; Carcinoma, Mucoepidermoid/mortality ; Carcinoma, Mucoepidermoid/pathology ; Carcinoma, Squamous Cell/diagnosis ; Carcinoma, Squamous Cell/mortality ; Carcinoma, Squamous Cell/pathology ; Cohort Studies ; Female ; Humans ; Kaplan-Meier Estimate ; Male ; Neoplasm Metastasis ; Neoplasm Staging ; Prognosis ; Retrospective Studies ; Salivary Gland Neoplasms/diagnosis ; Salivary Gland Neoplasms/mortality ; Salivary Gland Neoplasms/pathology ; Survival Rate
Language	English
Publishing date	2019-06-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	134792-5
ISSN	1432-1335 ; 0171-5216 ; 0084-5353 ; 0943-9382
ISSN (online)	1432-1335
ISSN	0171-5216 ; 0084-5353 ; 0943-9382
DOI	10.1007/s00432-019-02953-9
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Article ; Online: Integrative genotyping of cancer and immune phenotypes by long-read sequencing.

Penter, Livius / Borji, Mehdi / Nagler, Adi / Lyu, Haoxiang / Lu, Wesley S / Cieri, Nicoletta / Maurer, Katie / Oliveira, Giacomo / Al'Khafaji, Aziz M / Garimella, Kiran V / Li, Shuqiang / Neuberg, Donna S / Ritz, Jerome / Soiffer, Robert J / Garcia, Jacqueline S / Livak, Kenneth J / Wu, Catherine J

Nature communications

2024 Volume 15, Issue 1, Page(s) 32

Abstract: Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to ... ...

Abstract	Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural 'barcodes', we define the optimal targets for nanoranger, namely those loci close to the 5' end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.
MeSH term(s)	Humans ; Genotype ; High-Throughput Nucleotide Sequencing/methods ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Phenotype ; Gene Expression Profiling/methods
Language	English
Publishing date	2024-01-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44137-7
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Article ; Online: Hypothyroidism, autoimmunity and systemic characteristics of salivary tumors.

Israel, Yair / Rachmiel, Adi / Ziv, Gil / Nagler, Rafael

Oral oncology

2016 Volume 58, Page(s) e13–4

Language	English
Publishing date	2016-07
Publishing country	England
Document type	Letter
ZDB-ID	1120465-5
ISSN	1879-0593 ; 0964-1955 ; 1368-8375
ISSN (online)	1879-0593
ISSN	0964-1955 ; 1368-8375
DOI	10.1016/j.oraloncology.2016.05.003
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